Systematic review to evaluate the effects of oral antiretroviral pre-exposure prophylaxis (PrEP) in preventing HIV infection in HIV-uninfected persons at high risk of becoming infected. This is an update of a review originally published in 2009.(1)

Studies

Randomized controlled trials (RCT).

Population

Populations at high risk of HIV infection, e.g. commercial sex workers, individuals in serodiscordant relationships, injection drug users, men who have sex with men (MSM), sexually active young adults.

Intervention

Oral antiretroviral regimens including tenofovir (TDF) vs. placebo or no treatment; TDF with emtricitabine (FTC) vs. placebo or no treatment; TDF only versus TDF + FTC; or any other oral PrEP regimen.

Standard Cochrane HIV/AIDS Group search strategies were used, along with a range of relevant keywords and medical subject heading (MeSH) terms. There were no limits to language or publication status. Databases searched included the Cochrane Central Register of Controlled Trials, EMBASE, and PubMed, as well as online archives of major HIV/AIDS conference abstracts. The date range for the searches of the peer-reviewed literature was from January 1980 to April 2012. Archived conference abstracts were searched from 1985 to 2012. The World Health Organization (WHO)'s International Clinical Trials Registry Platform (ICTRP) and the National Institutes of Health's ClinicalTrials.gov were also searched for ongoing trials. The reviewers checked reference lists of included trials.

Searches, Screening and Data Extraction

One trial was included from the previous version of the review. A total of 2,684 new records were retrieved. Standard Cochrane methods were used in the screening process and in data collection. Two reviewers working independently identified 12 relevant studies, six of which were ongoing. Eight trials met the review's inclusion criteria, including one from the review's previous version.(2) Two of these trials had not yet been published in the peer reviewed literature,(3, 4) but the reviewers contacted investigators for necessary data. Two reviewers working independently extracted data from included trials.

HIV incidence: Four trials that compared TDF-FTC vs. placebo reported HIV incidence.(3, 4, 5, 7) All but one, "FEM-PrEP,"(4) showed a reduced HIV incidence, and the reviewers suggest that subjects in this trial's intervention arm were insufficiently adherent to TDF-FTC. In addition, the reviewers note that this trial had been stopped early for futility (relative risk [RR] 0.95, 95% CI 0.60 to 1.52).

In meta-analysis of the four trials, HIV incidence was significantly lower in subjects who received TDF-FTC (RR 0.51, 95% CI 0.30 to 0.86). There was substantial statistical heterogeneity (I2 =73%, p=0.01). One of the four trials was in an MSM population.(5) HIV incidence in this trial was reduced by 44% (RR 0.56, 95% CI 0.38 to 0.84). In meta-analysis on the three trials in heterosexual populations, HIV incidence was reduced by 53% (RR 0.47, 95% CI 0.21 to 1.08).

Two trials that compared TDF only vs. placebo reported HIV incidence.(1, 7) In meta-analysis of the two trials, HIV incidence was significantly lower in subjects who received TDF (RR 0.38, 95% 0.23 to 0.63). There was no significant statistical heterogeneity (I2 =0%, p=0.88).

In gender pre-specified subgroup meta-analysis,(3, 7) TDF-FTC significantly reduced new HIV infections in both men and women. However, TDF-FTC was marginally more efficacious in men (RR 0.18, 95% CI 0.08 to 0.43) than in women (RR 0.43, 95% CI 0.24 to 0.77) (p-value for interaction = 0.11).

Adherence: Reported adherence in the FEM-PrEP trial's intervention arm was 95%. Based on pill count, however, adherence was 86% in the intervention arm; measurement of TDF-FTC in blood levels suggested that adherence was significantly lower. Only 7/33 (21%) of HIV-infected subjects and 377/991 (38%) of uninfected subjects had detectable TDF-FTC in their blood. There was a similar disparity between reported adherence and objective measurements in the trial among MSM,(5) with a median range of 89-95% adherence after eight weeks, but TDF-FTC detectable in the blood of only 22/43 (51%) of HIV-uninfected subjects. Adherence by pill count in one trial(7) was 97%. Self-reported adherence in two trials(3, 6) ranged from 83.7%-84.1%. One trial did not report on adherence.(1)

Sexual behaviour: Two trials(5, 7) reported similar sexual practices across study arms, and one of these trials(5) reported no significant differences in the number of subjects with non-HIV sexually transmitted infections. Another trial1 described self-reported decreases in the number of coital acts per week and in the number of sexual partners in the past month, and self-reported increases in condom use.

Adverse events: All the TDF-FTC trials reported significantly higher rates of nausea and vomiting in the TDF-FTC arm vs. placebo. One trial5 reported the development of renal insufficiency in 26 subjects (2%) in its TDF-FTC arm vs. 15 (1%) in the placebo arm (p=0.08), which was reversible on discontinuation of the drug. Mild-to-moderate increases in alanine amino transferase (ALT) were noted in some subjects in another trial.(4) None of the other increases in study-related adverse events in any of the trials was statistically significant.

Conclusions

The reviewers conclude that the use of oral TDF alone or a TDF-FTC combination as pre-exposure prophylaxis reduces the risk of acquiring HIV in high-risk individuals.

Quality of the Evidence

The reviewers used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology(11) to assess evidence quality. GRADE ranks the quality of evidence on four levels: "high," "moderate," "low" and "very low." Evidence from randomised controlled trials starts at "high," but can be downgraded based on study limitations, inconsistency of results, indirectness of evidence, imprecision or for reporting bias. Evidence from observational studies starts at "low," but can be upgraded if the magnitude of treatment effect is very large, if there is a significant dose-response relation, or if all possible confounders would decrease the magnitude of an apparent treatment effect. Evidence from observational studies can also be downgraded. The reviewers found the quality of evidence to be moderate for the outcomes of HIV incidence and adverse events. The quality of evidence was graded down for imprecision, due to the small number of events in treatment arms. The reviewers did not perform GRADE analyses on the outcomes of adherence or sexual risk behavior.

Quality of the Review

This was a high quality systematic review. It meets every relevant criterion of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.(8)

In Context

Results from three of these trials were released by the New England Journal of Medicine on July 11, 2012.(9, 10, 11) The authors of this review were provided data by the investigators of these studies, so the publication of these studies does not change the review's conclusions.

Programmatic Implications

PrEP is an effective strategy for reducing an uninfected individual's risk of acquiring HIV infection through sexual transmission. However, it effectiveness is heavily dependent on high levels of adherence, which at least two of these trials found was difficult to achieve. Additionally the prevention benefit that accrues as the result of PrEP could potentially be outweighed if patients increase sexual risk taking. Nonetheless, together with early treatment of infected patients,12 oral and topical13 PrEP with TDF-FTC or TDF is an important new tool for preventing transmission. In an accompanying editorial in the New England Journal of Medicine, Cohen and Baden wrote, "The prevention of HIV infection is a critical global public health priority. Preexposure prophylaxis is emerging as part of an integrated HIV prevention strategy. The health care provider who recommends preexposure prophylaxis needs a management plan that recognizes the effects of this intervention on the patient's sexual behavior, safety and well-being as well as the ramifications of the intervention for the health of the public."(14)